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Werner Arber - Biographical

I was born on
June 3rd, 1929 in Gränichen in the Canton of Aargau,
Switzerland, where I went to the public schools until the age of
16. I then entered the gymnasium at the Kantonsschule Aarau where
I got a B-type maturity in 1949. From 1949 to 1953 I studied
towards the diploma in Natural Sciences at the Swiss
Polytechnical School in Zurich. It is in the last year of this
study that I made my first contacts with fundamental research,
when working on the isolation and characterisation of a new
isomer of Cl34, with a halflife of 1.5 seconds.

On the recommendation of my professor in experimental physics,
Paul Scherrer, I took an assistantship for electron microscopy at
the Biophysics Laboratory at the University of
Geneva in November 1953. This laboratory was animated by
Eduard Kellenberger and it had two prototype electron microscopes
requiring much attention. In spite of spending many hours to keep
the microscope "Arthur" in reasonable working condition, I had
enough time not only to help developing preparation techniques
for biological specimens in view of their observation in the
electron microscope, but also to become familiar with fundamental
questions of bacteriophage physiology and genetics, which at that
time was still a relatively new and unknown field. My first
contribution to our journal club concerned Watson and Crick's papers on the structure of
DNA.

In the 1950's the Biophysics Laboratory at the University of
Geneva was lucky enough to receive each summer for several months
the visit of Jean Weigle. He was the former professor of
experimental physics at the University of Geneva. After having
suffered a heart attack, he had left Geneva to become a
researcher at the Department of Biology of the California Institute of
Technology in Pasadena. There, he had been converted to a
biologist under the influence of Max
Delbrück and had chosen to study bacteriophage lambda.
This is why the first electron micrographs of phage lambda were
made in Geneva. Stimulated by Jean Weigle we soon turned our
interests also to other properties of lambda, and the study of
defective lambda prophage mutants became the topic of my doctoral
thesis.

In the summer of 1956, we learned about experiments made by Larry
Morse and Esther and Joshua
Lederberg on the lambda-mediated transduction (gene transfer
from one bacterial strain to another by a bacteriophage serving
as vector) of bacterial determinants for galactose fermentation.
Since these investigators had encountered defective lysogenic
strains among their transductants, we felt that such strains
should be included in the collection of lambda prophage mutants
under study in our laboratory. Very rapidly, thanks to the
stimulating help by Jean Weigle and Grete Kellenberger, this
turned out to be extremely fruitful. We could indeed show that
lambda-mediated transduction is based on the formation of
substitution mutants, which had replaced a part of the phage
genes by genes from the bacterial chromosome. This made the
so-called lambda-gal phage derivatives so defective that they
were not able any longer to propagate as a virus. In fact, one of
the at first sight rather frustrating observation was that
lysates of lambda-gal, which indeed could still cause the
infected host cell to lyse as does wild type phage lambda, did
not contain any structural components of lambda (phage particles,
heads or tails) discernible in the electron microscope. This was
the end of my career as an electron microscopist and in chosing
genetic and physiological approaches I became a molecular
geneticist.

After my Ph. D. exam in the summer of 1958 I had the chance to
receive an offer to work at the University of Southern California in Los
Angeles with Joe Bertani, a former collaborator of Jean Weigle.
Several years before, Bertani had isolated and characterised
another bacteriophage of E. coli, P1. Phage P1 rapidly had
become a very welcome tool of bacterial geneticists, since it
gives general transduction, i.e. any particular region of the
host chromosome gets at some low frequency wrapped into P1 phage
particles if P1 multiplies in a cell, and this enables the
geneticists to carry out linkage studies of bacterial genes.
While working as a research associate with Bertani, I received P1
at first hand which enabled me to study phage Pl-mediated
transduction of monomeric and dimeric lambda prophage genomes as
well as of the fertility plasmid F.

In the meantime, my Ph. D. thesis on lambda-gal, although written
in French, had been read, or, what is perhaps more essential,
understood in its conclusions by many leading microbial
geneticists.

This may be the reason why I received offers to spend additional
postdoctoral time in several excellent laboratories. On the other
hand, I had remained in close contact with Eduard Kellenberger,
and he urged me to come back to Geneva in order to lead an
investigation on radiation effects on microorganisms. As a
compromise, I decided to return to Geneva at the beginning of
1960, but only after having spent several very fruitful weeks at
each of the laboratories of Gunther Stent in Berkeley, Joshua
Lederberg in Stanford and Salvador
Luria at the Massachusetts Institute of Technology,
Cambridge.

At the end of the 1950's, a special credit had been voted for by
the Swiss Parliament for research in atomic energy, including
radiation effects on living organisms. Eduard Kellenberger felt
that important contributions to the latter questions could be
expected from studies with microorganisms, and he had therefore
submitted a research proposal which found approval by the
granting agency, the Swiss National Science Foundation. The project could
bring insight into the nature of radiation damage to genetic
material and its repair mechanisms, as well as of the stimulation
of genetic recombination by radiation. These topics had already
engaged the attention of Jean Weigle and Grete Kellenberger for a
number of years.

One of the first experiments after my return to Geneva was to
render E. coli B and its radiation resistant strain B/r
sensitive to phage lambda. The first step to accomplish this was
easy thanks to a hint received from Esther Lederberg to look for
cotransduction of the Ma1+ and lambdaS
characters. However, the strains thus obtained still did not
allow an efficient propagation of lambda. Very rapidly I realized
that this was due to host-controlled modification, a phenomenon
described for lambda and E. coli strains seven years
earlier by Joe Bertani and Jean Weigle. However, I was not
satisfied to know how to overcome this barrier. I was also
anxious to know how the restriction of phage growth and the
adaptation of lambda to the new host strain worked. When I
started investigations on the mechanisms of host-controlled
modification, I did not of course imagine that this sidetrack
would keep my interest for many years. Otherwise I might not have
felt justified to engage in this work because of its lack of
direct relevance to radiation research. However, a lucky
coincidence rapidly dissipated these concerns. At the same time,
Grete Kellenberger had looked at the fate of DNA from irradiated
phage lambda upon infection of host bacteria: part of it was
rapidly degraded after injection into the host. And so was the
DNA from unirradiated phage lambda used to measure adsorption and
DNA injection into restrictive bacterial strains! This phenomenon
became the topic of Daisy Dussoix's doctoral thesis, who very
carefully not only studied the DNA degradation of phage that was
not properly modified, but who also tried to detect parallels
between the fate of unmodified DNA in restrictive conditions and
of irradiated DNA in normal host cells.

Within about one year of study, it had become clear that
strain-specific restriction and modification directly affected
the DNA, without however causing mutations. It soon also became
obvious that restriction and modification were properties of the
bacterial strains and acted not only on infecting bacteriophage
DNA, but also on cellular DNA as manifested in conjugation
experiments. These findings were reported by myself and Daisy
Dussoix for the first time to the scientific community during the
First International Biophysics Congress held in Stockholm in the
summer of 1961. In a more extended version I presented them in
1962 to the Science Faculty of the University of Geneva as my
work of habilitation as privatdocent. This work earned me in the
same year the Plantamour-Prévost prize of the University of
Geneva.

At a time before the Swiss Universities received direct financial
help from the federal government, the Swiss National Science
Foundation awarded "personal grants" to qualified researchers to
allow them to guide projects of fundamental research at a Swiss
University. I was lucky to benefit from such a support form 1965
to 1970. These years were devoted to hard work to consolidate the
preliminary data and the concepts resulting from them, and to
extend the acquired notions, in particular with regard to the
mechanisms of modification by nucleotide methylation, with regard
to the genetic control of restriction and modification and with
regard to the enzymology and molecular mechanisms of these
reactions.

This work would not have been possible without a very fruitful
help by a large number of collaborators in my own laboratory and
of colleagues working on related topics in their own
laboratories. I was extremely lucky to receive in my laboratory
in the basement of the Physics Institute of the University of
Geneva a number of first class graduate students, postdoctoral
fellows and senior scientists. It is virtually impossible to list
them all in this context, but my warmest collective thanks go to
all of them. In 1964 Bill Wood laid out a solid basis for the
genetics of the restiction and modification systems EcoK
and EcoB. Later, Stuart
Linn, profiting from his fruitful contacts with Bob Yuan and
Matt
Meselson, who worked in the USA on the enzymology of
EcoK restriction, set the basis for in vitro studies with
EcoB restriction and modification activities. These
studies culminated in the final proof that modification in E.
coli B and K is brought about by nucleotide methylation. This
concept had found its first experimental evidence during my two
months' visit in 1963 with Gunther Stent at the University of
California in Berkeley. Several years later Urs Kühnlein, a
Ph. D student, and John Smith, working for various lengths of
time with us, succeeded in careful in vivo and in vitro
measurements on methylation to validate and extend the earlier
conclusions. Their experiments also brought important conclusions
with regard to the concept of the sites of recognition on the DNA
for the restriction and modification enzymes.

As an illustration that my work has not always been easy and
accompanied by success, I would like to refer to my long,
fruitless and thus largely unpublished attempts to find
experimental evidence for the diversification of restriction and
modification systems in the course of evolution. Systems
EcoK and EcoB form a closely related family as
judged from genetic and functional studies. Another family is
formed by restriction and modification systems EcoP1 and
EcoP15. One could expect that mutations affecting the part
of the enzymes responsible for recognition of the specificity
site on the DNA might result in new members of the family,
recognizing new specificity sites on DNA. We have in vain spent
much time in search for such evolutionary changes both after
mutagenization and after recombination between two members of the
same family of the above mentioned systems. That the basic idea
for this search was good was recently shown by Len Bullas,
Charles Colson and Aline van Pel (J. Gen. Microbiol. 95, 166-
172, 1976) who encountered such a new system in their work with
Salmonella recombinants.

In 1965 I was promoted extraordinary professor for molecular
genetics at the University of Geneva. Not only did I always enjoy
a continued contact with the students, but I also considered
teaching as a welcome obligation to keep my scientific interests
wide. Although we had a few excellent students in our
laboratories, the teaching of molecular genetics at the
University of Geneva in the 1960's suffered a bit from a lack of
interest by the young generation. This might have been related to
a more general lack of public interest for this field, which was
perhaps due to the economic structure of the city of Geneva and
its environments. These, at that time perhaps more subconscious
concerns, might have helped me to accept in 1968 an offer for a
professorship at the University of Basel, since I felt that more general
interest would be given to molecular genetics in this city with a
long tradition of biomedical research at its industries.

I started my new appointment at the University of Basel in
October 1971 after having spent one year as a visiting Miller
Research Professor at the Department of Molecular Biology of the
University of California in Berkeley. In Basel, I was one of the
first persons to work in the newly constructed Biozentrum, which houses several University
Departments, in particular those of Biophysics, Biochemistry,
Microbiology, Structural Biology, Cell Biology and Pharmacology.
This diversity within the same house largely contributes to
fruitful collaborative projects and it helps to keep horizons
broad both in research and teaching. Additional contributions to
this goal come from contacts with other nearby University
Institutes as well as with the private research Institutions in
the city.

Since my coming to Basel, I devoted relatively little of my time
to further studies on restriction and modification mechanisms.
Not that I have lost my interest in them. On the contrary, I was
fortunate to be able to set up a junior group which under the
leadership of Bob Yuan and more recently of Tom Bickle, became
rapidly quite independent, and it continues to be very successful
in its investigations on the more detailed aspects of the
molecular mechanisms of restriction and modification. This
allowed me to turn my main interests back to other mechanisms
affecting either positively or negatively the exchange of genetic
material. For a number of years Nick Gschwind, a Ph. D. student,
and Dorothea Scandella, a postdoctoral fellow, explored two other
mechanisms found in some E. coli strains or mutants and
affecting more specifically than restriction and modification
systems particular steps in the propagation of bacteriophage
lambda.

For the last several years I have turned my principal interests
to the intriguing activities of insertion elements and
transposons, which by their actions on genetic rearrangements,
seem to be the main driving forces of evolution in
microorganisms. Because of their independence on extended
nucleotide homologies these forces bring about exchange of
largely unrelated genetic materials. Our postdoctoral workers
Katsutoshi Mise, Shigeru Iida and Jürg Meyer brought
important contributions to the understanding of these phenomena,
mainly by the use of the bacteriophage P1 genome as a natural
vector of transposable elements. But general knowledge on this to
my mind extremely important field is still very scarce and
deserves continued attention.

Solid notions on naturally occurring genetic exchange between
organisms that are not directly related will also form a good
basis for a scientific evaluation of conjectural risks of in
vitro recombinant DNA research. Since this research largely makes
use of restriction enzymes, although it in no way fully depends
on them, I consider it a personal obligation to contribute to the
best of my abilities to the solution of questions which arose in
the scientific and public debate on this research in the last few
years. I see two ways to reach this goal. The first is scientific
and tends as just stated to better understand what nature does in
its nonhomologous genetic exchange. The second is rather
political and it consists in actions to stimulate continued
awareness of responsibility to work with a maximum of care in all
scientific investigations, which should, however, be allowed to
be done under optimal academic freedom.

A curriculum vitae would be incomplete without reference to my
private life. I am fortunate to have found a continued support
and steady encouragement by my family, in particular by my
parents, and, since we became married in 1966, by my wife
Antonia. In response to their interest and understanding for my
scientific activities, I have tried to give them my personal
affection needed for a harmonious life. Our two daughters Silvia
and Caroline were born in 1968 and in 1974, respectively. When
Silvia learned that I had been honored by the Nobelprize she not
only wanted to know what this is, but also why I was chosen as a
Laureate. After explaining her in simple terms the basic concepts
of the mechanisms of restriction enzymes, she, after some
reflection, reexpressed this message in her own terms by a tale,
which in the meantime has found wide diffusion around the world.
It might thus be justified to finish this curriculum vitae by its
reproduction:

"The tale of the king and his servants

When I come to the laboratory of my father, I usually see some
plates lying on the tables. These plates contain colonies of
bacteria. These colonies remind me of a city with many
inhabitants. In each bacterium there is a king. He is very long,
but skinny. The king has many servants. These are thick and
short, almost like balls. My father calls the king DNA, and the
servants enzymes. The king is like a book, in which everything is
noted on the work to be done by the servants. For us human beings
these instructions of the king are a mystery.

My father has discovered a servant who serves as a pair of
scissors. If a foreign king invades a bacterium, this servant can
cut him in small fragments, but he does not do any harm to his
own king.

Clever people use the servant with the scissors to find out the
secrets of the kings. To do so, they collect many servants with
scissors and put them onto a king, so that the king is cut into
pieces. With the resulting little pieces it is much easier to
investigate the secrets. For this reason my father received the
Nobel Prize for the discovery of the servant with the
scissors".

This autobiography/biography was written
at the time of the award and later published in the book series Les
Prix Nobel/Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted
by the Laureate.